Gene Tx Promising for Rare Brain Disease

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Gene therapy for Canavan disease appears safe long term and may help reduce brain atrophy and seizures associated with the hereditary enzyme deficiency.

Note that there were two serious adverse events in the study, but neither was judged related to the gene therapy itself.

Gene therapy for Canavan disease appears safe long term and may help reduce brain atrophy and seizures associated with the hereditary enzyme deficiency, an early-phase study showed.

Brain infusions of a virus to rewrite the mutated aspartoacylase gene resulted in no related adverse events over at least 5 years of follow-up in the 13 children treated in a phase I/II safety study by Paola Leone, PhD, of the University of Medicine & Dentistry of New Jersey in Stratford, and colleagues.

The treated patients showed less buildup of N-acetyl-aspartate (NAA) from lack of enzyme activity to break it down, which usually leads to degeneration of white matter in the brain, severe psychomotor delay, and an early death, the group reported in the Dec. 19 issue of Science Translational Medicine.

Progression of brain atrophy also slowed down compared with untreated patients, along with a modest reduction in seizure frequency and stabilization of overall clinical status.

"This is the first viral-based gene therapy for any neurological disease," Leone told MedPage Today. "It could be a cure in newly-diagnosed patients."

Viral-based gene therapy has been tried for brain tumors, restored partial vision for kids with an inherited retinal disorder, and has been approved for treatment of lipoprotein lipase deficiency in Europe, although none have reached approval for the U.S. market.

An earlier version of gene therapy for Canavan disease using a nonviral carrier had suggested partial reversal of elevated NAA levels, but viral vectors were developed with stronger gene expression capabilities that looked good in animal models.

So Leone's group tested it in a trial among 28 children, ages 3 months to 8 years, from the U.S., Brazil, England, Germany, Italy, and Venezuela who received gene therapy with an adeno-associated viral vector carrying the aspartoacylase gene.

All the cases had been definitively diagnosed with at least one positively identified gene mutation for typical (not mild) Canavan disease.

By comparison with the uniformly downward slope of levels after gene therapy, levels only went up among the 15 untreated patients in all brain regions except for the basal ganglia, "which had a flat or slightly negative slope but remained grossly elevated at more than twice the normal concentration."

Gene therapy was also associated with a switch from an upward to a downward trend in white matter T1 relaxation time in 10 of the 13 patients, "hinting at a more normal pattern of myelination," which is also affected by Canavan disease.

The other three patients included one who already had brain atrophy before treatment and two with severe disease.

The usual brain development in Canavan disease is normal growth of macroscopic structures and onset of myelination up to age 6 months, but then gradual vacuolation of white matter and hydrocephalus that accelerates after 12 months of age as NAA concentrations rise, the researchers pointed out.

Serial MRI monitoring indicated that brain atrophy slowed down or even reversed in some treated patients. Some also showed a stabilization of loss of white matter mass.

Canavan disease also is associated with severe truncal hypotonia and instability, lack of head support, and limb spasticity, and gene therapy was associated with an improvement in ability to roll from prone to supine position (P=0.017).

Gross motor function improvement was less in the children who were oldest at the time of treatment.

Likewise the level of alertness improved for treated children after excluding the three oldest (P=0.002), again suggesting that younger children had a somewhat better response to gene therapy, similar to what was seen with the retinal gene therapy.

"Normalization of NAA at a very early age may be necessary to prevent irretrievable dysmyelination, motor delay, and mental retardation in Canavan disease," the researchers suggested.

Seizure frequency dropped (P<0.001), and 11 of the 13 treated patients were able to decrease their anti-epileptic medications. All four on anti-spasmodic medications decreased or discontinued these due to improvements in resting tone.

Rigidity, spasticity of the lower limbs, social function, and language scores also showed some signal for benefit.

There were two serious adverse events: one low-grade fever after surgery that prolonged hospitalization, and a case of postoperative brain abscess and bacteremia. Neither was judged related to the gene therapy itself.

Most patients had self-limiting fever and a little hemorrhage after the operation to administer gene therapy. Two developed bilateral chronic subdural hematomas that resolved on their own without drainage.

All patients are still alive, now at ages 6 to 17 years.

The study's one major limitation was it wasn't possible to target the cerebellum or brainstem because it was physically separated from supratentorial sites of gene transfer, the authors explained.

"Future gene therapy interventions for Canavan disease should focus on the neonatal age range (0 to 3 months) before irreversible structural changes have occurred, using newer vectors that target oligodendrocytes or a mixed target cell population including glia, neurons, and arachnoid cells," the group wrote.

Higher vector doses, more injection sites, and a phase III trial are also goals, Leone noted in an interview.

"The limiting factor for now is funding," she explained, pointing out that the small number of affected patients worldwide has limited interest from biotech companies and could hurt the treatment's chances in reaching the commercial market.

The study was supported by the NINDS, with additional funding from the Canavan Research Foundation, Canavan Research Illinois, Jacob's Cure, the National Endowment for Alzheimer's Research, and the Ralph and Lois Silver Foundation.

One co-author reported holding patents on AAV vector production and applications.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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